Surface-enhanced, Raman-scattering (SERS)-based probes, consisting of nano-structured particles, are emerging for biomedical applications. The SERS effect is typically prominent in nanoscale metal-dielectric environments in which the signal of a proximal organic molecule can be rationally tailored and enhanced to the extent that single molecules may be detected. Hence, SERS probes typically contain nanoscale metallic structures and organic molecules that act as quantitative reporters for the presence of the probe.
The achieved enhancement depends on the reporters' molecular characteristics as well as nanoscale size, shape, geometry, local aggregation state and surface characteristics of the metal. These parameters can potentially be controlled to tune the reporter's signal, especially to maximize sensitivity of detection. Controlling and tuning the enhancement of the reporter's signal, however, is an ongoing challenge. Given the large number of factors influencing enhancement, designing particles for specific enhancement levels remains an active theoretical challenge while simultaneously controlling variability in their response remains a practical hurdle. Variability in SERS signal arises due to the synergistic effects of the metal's atomic mobility, surface reorganization and the reporter's molecular mobility. The net result is an unpredictable variation in enhancement, including blinking or “hot-spots.” The intractability of controlling enhancement has led to theorization of a “SERS-uncertainty principle”1 and a practical choice between (a) unstructured colloids providing an exceptionally large but uncontrolled enhancement and uncertain spatial localization or (b) well-defined and controlled probes using self-assembling monolayer reporters but of substantially lower enhancement and limited reported diversity. While the utility of controlled nanostructures on making the SERS effect usable is not disputed, a rational framework to design SERS probes for a desired enhancement level, spectral selectivity, and size is lacking.